Role of DEPTOR in T Cell Activation and Alloimmunity

项目总结/摘要 同种异体移植排斥反应的特征是效应CD 4 + T细胞对供体抗原的应答激活， 细胞和体液对移植物的强烈攻击然而，CD 4 + T细胞内的多种细胞内信号 同时起作用以增强CD 4 + Foxp 3 + T调节细胞的扩增和功能， 共同用于控制同种免疫应答。此外，这一过程的潜力 免疫调节预防和抑制同种免疫T效应细胞活化和排斥。重要的是， 最近的进展表明，CD 4 + Foxp 3 + T细胞的分化和功能是负调控的， mTOR，特别是mTORC 1的细胞内在活性。然而，人们对监管知之甚少。 同种异体反应性CD 4 + T细胞效应子内的细胞内mTOR信号传导，或其相对活性如何可能与 在Foxp 3+亚群中被调节，或者是否可能利用调节信号来增强 在病理状态下调节生理性Treg活性以预防疾病，包括慢性炎症的发展。 同种异体移植排斥反应。DEPTOR是最近发现的调节mTOR诱导的细胞内因子， 在高度增殖的癌细胞中的信号应答，并且最近已经观察到它在高度增殖的癌细胞中起作用。 包括血管内皮细胞在内的正常细胞类型。在初步研究中，我们发现DEPTOR是 在未活化的CD 4 + T细胞中以高水平表达，并且进一步地，其表达在 细胞活化此外，我们发现DEPTOR的强制性过表达调节了CD 4 + T细胞， 体外激活反应，促进免疫调节和完全MHC后的移植物存活 体内错配移植。我们认为，这些意见确定DEPTOR作为一个关键的 CD 4 + T细胞活化的上游细胞内调节剂以及表型和功能结果 同种免疫反应我们在本R 01中的目标是使用以下方法进一步评估这些观察结果： 新型转基因小鼠，以及1）定义DEPTOR在CD 4 + T效应器和调节中的选择功能 2）评估CD 4 + T细胞DEPTOR表达在体内模型中的结果， 移植排斥反应我们将检验DEPTOR是一种细胞内在分子的假设， CD 4 + T效应细胞活化和增强CD 4 + T调节细胞功能以增强免疫调节 并促进移植物的长期存活。我们提出了两个具体目标，我们将：1），确定 CD 4 + T细胞亚群中细胞内在DEPTOR功能的后果和机制，和2）， 确定CD 4 + T细胞DEPTOR在长期同种异体移植物存活中的功能。这些创新的 研究将具有广泛的科学和生物学意义， 移植免疫生物学

Project Summary/Abstract Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an intense cellular and humoral attack on the graft. However, multiple intracellular signals within CD4+ T cells operate co-incidentally to enhance the expansion and function of CD4+Foxp3+ T regulatory cells that collectively serve to control the alloimmune response. Furthermore, the potency of this process of immunoregulation prevents and restrains alloimmune T effector cell activation and rejection. Importantly, recent advances indicate that CD4+Foxp3+ T cell differentiation and function is negatively regulated by the cell intrinsic activity of mTOR and specifically mTORC1. However, little is known about the regulation of intracellular mTOR signaling within alloreactive CD4+ T cell effectors, or how its relative activity may be modulated in Foxp3+ subsets, or whether it is possible to exploit modulatory signals to augment physiological Treg activity in pathological states to prevent disease, including the development of chronic allograft rejection. DEPTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced signaling responses in highly proliferative cancer cells, and it has more recently been observed to function in normal cell types including vascular endothelial cells. In preliminary studies, we find that DEPTOR is expressed at high levels in unactivated CD4+ T cells, and further, that its expression is reduced upon cellular activation. In addition, we find that forced overexpression of DEPTOR modulates CD4+ T cell activation responses in vitro, promotes immunoregulation and prolongs graft survival following fully MHC mismatched transplantation in vivo. We suggest that these observations identify DEPTOR as a critical upstream intracellular modulator of CD4+ T cell activation as well as the phenotypic and functional outcome of the alloimmune response. Our objectives in this R01 are to further evaluate these observations using novel transgenic mice, and 1), define the select function of DEPTOR in CD4+ T effector and regulatory subsets in vivo, and 2), evaluate the consequences of CD4+ T cell DEPTOR expression in models of transplant rejection. We will test the hypothesis that DEPTOR is a cell intrinsic molecule that modulates CD4+ T effector cell activation and augments CD4+ T regulatory cell function to enhance immunoregulation and promote long-term graft survival. We propose two specific aims in which we will: 1), determine the consequences and mechanism of function of cell intrinsic DEPTOR in CD4+ T cell subsets, and 2), determine the function of CD4+ T cell DEPTOR in long-term allograft survival. Collectively, these innovative studies will have broad scientific and biological implications of great significance and relevance to transplantation immunobiology.